This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Since viruses generate rapidly and have high mutation rates, they can quickly adapt to new host and develop vaccine resistance, making an understanding of the mechanisms for adaptive evolution important for human health. The proposed research is a systematic approach to elucidate molecular mechanisms behind adaptive protein evolution in bacteriophage. We will utilize computer simulations to quantitatively estimate the effect of single amino acid changes on protein interactions and stability, and thus provide insight into the mechanisms of adaptive evolution. We will investigate the possible correlation between changes in fitness and binding affinity. The proposed research will provide detailed insight into the molecular mechanisms responsible for adaptive protein evolution in bacteriophage. This research has the potential to pave the way for predictive relationships between protein stability and biological fitness, which would improve our ability to understand and respond to viral adaptation. A long-term goal of the proposed research is to suggest possible new adaptive mutations that have not been seen experimentally. Preliminary data obtained during the funding period will be used to generate an R01 proposal to the National Institutes of Health.